Novel substituted tetrahydropyridines



United States Patent NOVEL SUBSTITUTED rErRAnYnRorYnmmEs Albert Pohland,Indianapolis, Ind, asslgnor to Eli Lilly alggi Company,'lndianapolis,Ind a co 'lm' flon of ans No Drawing. Filed Aug. 16, 1951, Se!- No. man6 Claims. 01. 260-295) This invention relates to novel substitutedtetrahydropyridines. More particularly it relates to oxygenatedphenethyl-substituted tetrahydropyridines.

The compounds provided by this invention are represented by thefollowing formula:

wherein R, R and R are chosen from the group consisting of hydrogen,hydroxy, and lower alkoxy and lower alkylcarbacyloxy radicals in whichthe alkyl groups have from 1 to 3 carbon atoms, and not more than two ofR, R and R are hydrogen. Thus when R, R and R, represent lower alkoxygroups they can be illustratively methoxy and ethoxy and when theyrepresent lower alkylcarbacyloxy radicals in which the alkyl groups havefrom 1 to 3 carbon atoms, they canvbe, illustratively, acetoxy,propionoxy and butyroxy radicals. Also included in this invention arethe pharmaceutically-acceptable acid addition salts of compounds comingwithin the scope of the above formula.

Illustrative compounds provided by this invention include 1 homoveratryl4 phenyl 1,2,3,6 tetrahydropyridine hydrochloride, 1 homopiperonyl 4--phenyl- 1,2,},6 tetrahydropyridine hydrochloride, 1 homovanillyl"- 4phenyl l,2,3,6 tetrahydropyridine hydr'obrm mide, 1 (4 acetoxyphenethyl)4 phenyl 1,2,31,6- tetrahydropyridine sulfate, 1 (4 acetoxy 3methoxyphenethyl) 1,2,3,6 tetrahydropyridine maleate, 1-(3-ethoxyphenethyl) 4 phenyl l, 2, 3, 6 tetrahydrok pyridine succinate, and1 (3,5-dihydroxyphenethyl) 4 phenyl-1,2,3,6-tetrahydropyridinehydrochloride. It will be apparent to those skilled in the art thatcertain substituting groups, for example, lower alkyl radicals, can bepresent in positions in the molecule other than those specified above,as for example, in the a-position of the tetrahydropyridine ring.

The novel compounds provided by this invention are characterized by aphysiological action of marked central depressant activity of selectedcharacter; that is, the compounds have a pronounced activity on thecentral nervous system in their abilityto depress transmission of nerveimpulses across synapses mediated by endogenous sympathetic agents. Theabove physiological action makes them useful in treating mammals toprovide neurosedation and to reduce hypertension. Additionally thecompounds show anti-pyretic, anti-inflammatory and antiemetic activity.v

For administration to humans and animals, the tetrahydropyridines ofthis invention can be compounded into the various pharmaceutical formscommonly employed in the art, such as tablets, capsules, solutions andelixlrs.

.The novel tetrahydropyridine compounds are generally employed in theform of a pharmaceutically acceptable acid addition salt since the saltforms are preferred by "2,967,182 Patented Jan. s, 1961 reason ofincreased solubility and stability, decreased volatility, greateradaptability to compounding, etc. Pharmaceutically acceptable. acidsuseful in forming salts with the above compounds are those acids whichdo not markedly increase the toxicity of the salt,over

that of the free base. Among the pharmaceutically acceptable acids whichcan be employed for this purpose are inorganic acids suchashydrochloric, hydrobromic, sulfuric and phosphoric acids, and organicacids such as maleic, benzoic, succinic and citric acids. The! acidaddition salts of the free bases of this invention are in general whitecrystalline solids melting above 100' C. The free bases from which theyare derived are high boiling viscous oils or low melting crystallinesolids having a typical amine odor.

The compounds of this invention can readily be prepared by alkylating4-phenyl-1,2,3,6-tetrahydropyridine with a phenethyl halide which isappropriately substituted. For example, the reaction of4-phenyl-1,2,3,6-tetrahydropyridine with homoveratryl chloride yieldsthe hydrochloride salt ofl-homoveratryl-4-phenyl-l,2,3,6-tetrahydropyridine. Those compounds inwhich R, R or R, represent hydroxy or alkylcarbacyloxy radicals can alsobe The hydroxy-substituted tetrahydropyridine so produced. can, ifdesired, be acylated by conventional methods toyield atetrahydropyridine substituted with one or more= alkylcarbacyloxygroups.

This invention is further illustrated by the following;

specific examples.

EXAMPLE 1 Preparation of1-homoveratryl-4-phenyI-1,2,3,6-tetrahydropyridine A reaction mixturecontaining 16 g. of 4-phenyl-l,2,3,6'

tetrahydropyridine, 24.6 g. of homoveratryl bromide, 200 ml. of ethanoland 25.2 g. of sodium bicarbonate was heated with stirring at refluxingtemperature for about three hours. The solvents were then removed fromthereaction mixture by evaporation in vacuo. About 200 ml. of water andabout 20 ml. of 5 N sodium hydroxide were added to the residue whichcontained l-homoveratryl-4-phenyl-l,2,3,6-tetrahydropyridine formed inthe above reaction. The alkaline, aqueous mixture was extracted with two100 ml. portions of chloroform, and one 100 ml. portion of ether. 1homoveratryl 4 -phenyll,2,3,6-tetrahydropyridine, being insoluble in thealkaline solution, was extracted into the organic solvent layers whichwere separated in each instance. The separated layers were combined anddried and the solvents were removed therefrom by evaporation in vacuo.The white residue, comprising1-homoveratryl-4-phenyl-1,2,3,6-tetrahydropyridine melted at aboutl10-11l C. after being recrystallized from an ethyl acetate-hexanesolvent mixture. l-homoveratryl-4-phenyl-l,2,3,6-tetrahydropyridinehydrochloride was prepared by passing gaseous hydrogen chloride into anacetone solution of the free base. After two recrystallizations fromethanol it melted with decomposition at about 242-243 C.

A'nalysis.Calculated for Cg1Hg5NO3'HCl: C, 70.08; i H, 7.22. Found: C,70.03; H, 7.28.

, EXAMPLE 2 Preparation of I-(3,4-dihydroxyphnethyl) -4-phenyl-1,2,3,6-tetrahydropyridine A mixture containing 10 g. ofl-homoveratryl-4-phenyll,2,3,6-tetrahydropyridine and 200 ml. of glacialacetic acid saturated with gaseous hydrogen bromide was heated at aboutC. for about four hours. The solvents were i acamaaethyl)-4-phenyl-l,2,3,6-tetrahydropyridine hydrobromide precipitated andwas isolated by filtration. The filter cake was recrystallized from amixture of methanol and ethyl acetate,1-(3,4-dihydroxyphenethyl)-4-phenyl'-1,2,3 ,6-tetrahydropyridinehydrobromide thus prepared melted at about 257-258 C.

Analysis.Calculated: C, 60.64; H, 5.89; N, 3.72; Br, 21.24. Found: C,60.48; H, 6.01; N, 3.54; Br, 21.70.

EXAMPLE 3 Preparation of 1-(3,4-diacetoxyphenethyl) -4-phenyl- 1,2,3,6-tetrahydrpyridine About 2.5 g. of1-(3,4-dihydroxyphenethyl)-4-phenyl- 1,2,3,6-tetrahydropyridinehydrobromide were mixed with 60 ml. of acetic anhydride and the mixturewas refluxed for about 1 hour. The excess acetic anhydride was removedby evaporation in vacuo. The solid residue comprised 1(3,4-diacetoxyphenethyl)-4-phenyl-l,2,3,6-tetrahydropyridinehydrobromide. This compound melted at about 214-215" C. afterrecrystallization from a methanol-acetone solvent mixture.

Analysis.Calculated: C, 60.00; H, 5.69; Br, 17.38. Found: C, 60.20; H,5.90; Br, 17.42.

EXAMPLE 4 Preparation of 1-(3,4-dipr0pi0noxyphenethyl) -4-phenyl-1,2,3,6-tetrahydropyridine EXAMPLE 5 Preparation of1-(3,4-dibutyroxyphenethyl) -4-phenyl- 1 ,2,3,6-tetrahydropyridine Areaction mixture was prepared containing 1 g. of 1-(3,4-dihydroxyphenethyl) -4-phenyl-1,2,3,6 tetrahydropyridine, 3 ml. ofn-butyryl chloride, ml. of pyridine and 10 ml. of benzene. The free1-(3,4-dihydroxyphenethyl 4 phenyl-1,2,3,6-tetrahydropyridine base wasprepared from the hydrobromide salt by dissolving the salt in water,making the water solution alkaline with ammonium hydroxide andextracting the thus formed free base into benzene. The benzene wasevaporated from the extraction mixture in vacuo, leaving the free baseas a residue. The reaction mixture prepared as above was allowed toremain at ambient room temperature for about 16 hours after which timethe volatile constituents were removed by evaporation in vacuo. Theresidue containing1-(3,4-dibutyroxyphenethyl)-phenyl-4-1,2,3,6-tetrahydropyridinehydrochloride was dissolved in water. The water layer was washed withabout 50 ml. of ether and the ether wash was discarded. The water layerwas made alkaline with 10 percent concentrated ammonium hydroxide thusforming 1-(3,4-dibutyroxyphenethyl)-4-phenyl- 1,2,3,6-tetrahydropyridinefree base. The free base, being insoluble in the alkaline layer, wasextracted therefrom by three successive 50 ml. portions of ether. Theether extracts were combined, were washed once with water and weredried. The drying agent was removed by filtrasodium hydroxide and 14 ml.of water.

tion and the filtrate was saturated with gaseous hydrogen chloride toform 1(3,4-dibutyroxyphenethyl)-4-phenyll,2,3,6-tetrahydropyridinehydrochloride. The ether was removed from the mixture byevaporation invacuo and the residue was crystallized from an acetone-ethyl acetatesolvent mixture. 1-(3,4-dibutyroxyphenethyl)-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride thus prepared melted at about192 C. after being twice recrystallized from a methanol-ethyl acetatesolvent mixture.

Analysis.--Calculated: C, 67.80; H, 7.26; Cl, 7.51. Found: C, 68.97; H,7.44; Cl, 7.35.

EXAMPLE 6 Preparation of1-h0movanillyl-4-phenyl-1,2,3,6-tetrahydropyridine 11.0 g. of4-benzyloxy-3-methoxyphenyl acetic acid and 20 ml. of thionyl chloridewere mixed and the mixture was warmed at about 40 C. for about one hour,thus forming 4-benzyloxy-3-methoxyphenylacetyl chloride. The excessthionyl chloride was removed in vacuo. The substituted phenylacetylchloride remaining as a residue was dissolved in about 30 ml. ofbenzene. To this solution was added a solution containing 3.3 g. of 4-phenyl-4-hydroxy piperidine in 30 ml. of pyridine. The mixturewas heatedat about C. for about one hour and was then allowed to stand at ambientroom temperature for about 16 hours. The solvents were removed byevaporation in vacuo. The residue comprising N-(4-benzyloxy-3-methoxyphenylacetyl)-4-phenyl-4 hydroxypiperidine dissolvedin ether. The ether layer was washed successively with 5 percenthydrochloric acid, 5 percent sodium bicarbonate and water. The washedether layer was dried over magnesium sulfate and the drying agent wasremoved by filtration. The filtrate was added to a suspension of 3.8 g.of lithium aluminum hydride in 100 ml. of ether. After the addition hadbeen completed, the reaction mixture was heated at about 35 C. for onehour. Next, the reaction mixture was decomposed by successive additionof 4 ml. of water, 3 ml. of 20 percent The resulting mixture wasfiltered and the filtrate which contained l-(4- benzyloxy 3methoxyphenethyl)-4-phenyl-4-hydroxypiperidine formed in the abovereaction was evaporated to dryness. The residue comprisingl-(4-benzyloxy-3- methoxyphenethyl)-4-phenyl-4-hydroxy piperidine wasdissolved in about 220 ml. of 6 N hydrochloric acid, and the resultingsolution was heated at refluxing temperature for six hours in order todebenzylate and dehydrate the compound, thus forming1-homovanillyl-4-phenyl- 1,2,3,6-tetrahydropyridine as the hydrochloridesalt. The reaction mixture was then evaporated to dryness. The resultingresidue was crystallized from an ethyl acetatemethanol mixture yieldingl-homovanillyl-4-phenyll,2,3,6-tetrahydropyridine hydrochloride meltingat about 203-204 C.

1-homovanillyl4-phenyl-1,2,3,6 tetrahydropyridine prepared as above canbe acetylated by the procedure of Example 3 to yield1-(4-acetoxy-3-methoxyphenethyl)- 4-phenyl-1,2,3,6-tetrahydropyridinemelting at about 231- 232 C.

EXAMPLE 7 Preparation of J (4 methoxyphenethyl) 4 phenyl-1,2,3,6-tetrahydropyridine Following the procedure of Example 1,4-methoxyphenethyl bromide and 4-phenyl-1,2,3,6-tetrahydropyridine werereacted together in ethanol solvent in the presence of sodiumbicarbonate, thus forming 1-(4- methoxyphenethyl)-4-phenyl-1,2,3,6tetrahydropyridine. This compound was isolated as the hydrochloride saltwhich after being twice recrystallized from a methanolethyl acetatesolvent mixture melted at about 2l6217 C.

1 (4-hydroxyphenethyl)-4-phenyl-1,2,3,6-tetrahydropyridine and1-(4-acetoxyphenethyl)-4-phenyl-l,2,3,6- tetrahydropyridine can beprepared from 1-(4-methoxy 5 vphenethyl)-4-pheny1+1,2,3,6-tetrahydropyridine by following theprocedures of Examples 2 and 3 respectively.

I claim:

addition salts thereof, said substituted tetrahydropyridine beingrepresented by the following formula:

wherein R, R; and R, are chosen trom the group consisting of hydrogen,hydroxy, and lower alkoxy and alkyl- 15 2,748,140

carbacyloxy radicals in which the alkyl groups have from *1 to 3 carbonatoms, and from zero to. two of R, R and dine.

3. 1-(3,4-dihydroxyphenethyl)-4-pheny1-1,2,3,6 tetrahydropyridine. 4.l-(3,4-diacetoxyphenethyl)-4-phenyl-1,2,3,6 tetrahydropyridine.

5. 1-(3,4-dipropionoxyphenethyD-4-pheny1 1,2,3,6- tetrahydropyridine.

6. l-homovanillyl-4-phenyl-l,2,3,6-tetrahydropyridine.

References Cited in the file of this patent UNITED STATES PATENTSSchmidle et a1 May 29, 1956 2,784,192 Schmidle et a1. Mar. 5, 1957

1. A COMPOUND OF THE CLASS CONSISTING OF A SUBSITUTED TETRAHYDROPYRIDINEAND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, SAIDSUBSTITUTED TETRAHYDROPYRIDINE BEING REPRESENTED BY THE FOLLOWINGFORMULA